1. FIELD OF THE INVENTION
The present invention is directed to novel and useful derivatives of theophylline, a known drug useful in the treatment of asthma. More particularly, the present invention is directed to certain "pro-drug" forms of theophylline useful in the treatment of asthma in warm-blooded animals, e.g. humans.
For the purposes of this application, the term pro-drug denotes a derivative of a known and proven prior art compound (i.e., theophylline) which derivative, when administered to a warm-blooded animal, "cleaves" in such a manner as to release the proven drug form and permit the same to attain a sustained therapeutic level for a longer period of time than that which could be attained if the proven drug form per se was administered. More specifically, because of the very low water solubility and low dissolution rate of the pro-drug forms of this invention, such forms enable theophylline to be released quite slowly thus permitting therapeutic blood levels of the same to be maintained over an extended period of time, while at the same time, avoiding non-toxic blood levels of theophylline to be reached. The pro-drug forms of this invention are cleaved so rapidly in aqueous solution that the pro-drug form per se does not reach the bloodstream, but rather, cleavage of the pro-drug occurs before and/or during the absorption process. As such, substantial and sustained bioavailability is assured.
2. DESCRIPTION OF THE PRIOR ART
Theophylline, normally administered as the ethylenediamine salt (Aminophylline) or choline salt, is a useful and potent bronchodilator commonly prescribed for the treatment of bronchial asthma. Because it is readily soluble, Aminophylline has for many years been accepted as an effective bronchodilator when given orally. However, Aminophylline in solution becomes highly alkaline and is hydrolized by the gastric juice with resultant gastric irritation from the free theophylline liberated.
5 to 12 mcg./ml of whole blood or 10 to 25 mcg./ml of plasma are the relative blood levels of theophylline generally accepted as necessary to achieve effective bronchodilation. See, E. G. Truitt, V. A. McKusick, J. C. Krantz, Jr; Pharm. Exp. Ther., 100, 309 (1950) and M. Warwick Turner; Brit. Med. Jr., 2, 67 (1957), respectively. These theophylline blood levels are, however, difficult to attain, since as a result of the gastrointestinal upset experienced, patients cannot tolerate an adequate therapeutic dose of the drug. Reports in the literature with a variety of theophylline derivatives have often shown not only that theophylline blood levels achieved are below the values required for the relief of a bronchospasm, but also that even when these therapeutic levels are obtained, they fall off extremely rapidly in the first few hours following administration of the drug. Thus, repeated dosing of the patient abot every 3 to 4 hours is necessary. See, E. G. Truitt, V. A. McKusick, J. C. Krantz, Jr., and M. Turner-Warwick, and R. H. Jackson, J. I. McHenry, S. B. Moreland, W. J. Raymer, and R. L. Etter; Dis. Chest., 45, 75 (1964), and J. Schluger, J. T. McGuinn, and D. J. Hennesey; Amer. J. Med. Sci.: 233, 296 (1957), respectively.
In addition, even when therapeutic blood levels of theophylline are achieved, the amount of theophylline administered to a patient is so excessive that the therapeutic blood level achieved approaches and often reaches toxicity.
In one attempt to overcome the above disadvantages associated with administering theophylline, certain individuals have prepared a continuous-release formulation, such that the release rate of theophylline is dependent upon the formulation medium into which it is incorporated. That is, sustained therapeutic blood levels of theophylline are achieved through the use of a particular pharmaceutical formulation rather than chemical modification of the theophylline molecule. See, C. Boroda, R. B. Miller, S. T. Leslie, E. G. Nicol and I. Thompson; Clin. Pharm., 383 (1973) and D. McIntosh, Brit. J. Clin. Pharm., 12, 233 (1971) respectively.
Some theophylline derivatives, analogous to the compounds of formula (I) described hereinabove, have been prepared and described in the literature for the purpose of studying their chemistry per se, without any indication of any pharmaceutical utility. For instance, 7-acetyltheophylline was reported in three different articles. See, for instance, T. Higuchi, H. K. Lee and Ian H. Pittman; Farm. Aikak., 80, 55 (1971) and Y. Ishido, A. Hosono, S. Isome, A. Maruyama, and T. Sato; Bull. Chem. Soc. Japan, 37, 1389 (1964), respectively.
7-acetyltheophylline and 7-benzoyltheophylline were reported in H. Biltz, and K. Struffe, Ann., 404, 170 (1914) as well.
7-propionyltheophylline and 7-butyryltheophylline have also been reported in the literature. See, Y. Ishido, A. Hosono, S. Isome, A. Maruyama, and T. Sato, supra.
Finally, U.S. Pat. No. 2,729,643 discloses certain 7-carboxamidotheophylline derivatives useful as diuretics.
As for the compounds of formula (II) described herein above, no prior art of structural chemical or pharmacological significance is known.